PROJECT SUMMARY Cellular shape change is a fundamental characteristic of metazoan cells that is key to development, physiology, and pathology. The formation and plasticity of neural networks are key examples of cell shape change during development and physiology, whereas cell shape and motility goes awry in cancers such as melanoma. The active control of the cytoskeleton is acknowledged as critical to cellular shape change, whereas the concurrent remodeling of the plasma membrane is perhaps less well appreciated. Although many cytoskeletal and membrane remodeling components are known and their biochemical and structural characteristics described, we lack a systematic understanding of how these disparate systems are regulated and coordinated to orchestrate cellular shape change. Perhaps the most important problem in cell morphogenesis is understanding how cells perceive cues in their environment and convert this extracellular information into shape changes through coordinated cytoskeletal dynamics and plasma membrane remodeling. Functions of small GTPases and kinases are well studied in regulating cytoskeletal dynamics and membrane remodeling. Work from my lab identified an emerging role for E3 ubiquitin ligases in regulated cellular shape change. We identified two E3 ubiquitin ligases, TRIM9 and TRIM67, which regulate cytoskeletal and exocytic proteins and cellular shape changes in response to netrin. Netrin is an extracellular morphogen that promotes neuronal morphogenesis and the progression of cancers, such as melanoma. TRIM9 and TRIM67 thus provided an excellent entry point for the lab to investigate how cytoskeletal and membrane remodeling are coordinated during netrin triggered morphogenesis and motility. TRIM9 and TRIM67 share similar sequences, localization, and interaction partners, however our studies identified distinct functions of these related proteins and antagonistic phenotypes associated with their deletion. The overarching goal of this program is to test the hypothesis that TRIM9 and TRIM67 coordinate cytoskeletal dynamics and exocytosis during netrin-dependent morphogenesis in neurons and migrating melanoma cells. Our work will provide fundamental mechanistic understanding of the regulation of the cytoskeleton and membrane trafficking during development and metastasis.